Our overall objective is to study the biochemistry, physiology, and histopathology of the various diabetic, prediabetic, and obese stocks of mice available at the Jackson Laboratory, in the hope of establishing the primary lesion involved in each of these phenotypically similar genetic obesities. The specific aims of this project are: to establish the site and mechanism of action of the two obesity genes, diabetes (db) and obese (ob), that cause obesity or obesity coupled with severe diabetes on the genetic background in which the specific gene is expressed; to establish the number of modifying genes in the background genome responsible for the change from an obesity to a diabetic syndrome and, if possible, to establish their sites of action; to compare the effects of diabetes and obese with yellow (Ay) viable yellow (Avy) and fat (fat) which also cause hyperphagia, obesity, and some diabetic symptoms; to initiate biochemical and physiological studies on primary cultures of islets obtained from normal mice and mice homozygous for obese (ob) and diabetes (db); and to use these cultures to see if the action of the modifying genes in the C57BL/KsJ background involves a defective endocrine pancreas unable to maintain either adequate synthesis or secretion of insulin in response to a prolonged metabolic insult.